title: Activating mutations of GNAS in canine cortisol-secreting adrenocortical tumors.
abstract: BACKGROUND
  Cushing's syndrome or hypercortisolism is a common endocrinopathy in dogs. In approximately 15% of cases, the disorder is caused by adrenocorticotropin (ACTH)-independent hypersecretion of cortisol by an adrenocortical tumor (AT). Without other explanation, the cortisol hypersecretion has been referred to as autonomous.
  
  
  OBJECTIVE
  To investigate whether ACTH-independent hypersecretion of cortisol may be associated with aberrant activation of the melanocortin 2 receptor (MC2R)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway.
  
  
  METHODS
  All analyses were performed on 44 cortisol-secreting ATs (14 adenomas and 30 carcinomas) derived from dogs diagnosed with ACTH-independent hypercortisolism.
  
  
  METHODS
  Mutation analysis was performed of genes encoding the stimulatory G protein alpha subunit (GNAS), MC2R, and PKA regulatory subunit 1A (PRKAR1A) in all ATs.
  
  
  RESULTS
  Approximately one-third of all ATs harbored an activating mutation of GNAS. Missense mutations, known to result in constitutive activation, were present in codon 201 in 11 ATs, in codon 203 (1 AT), and in codon 227 (3 ATs). No functional mutations were found in MC2R and PRKAR1A.
  
  
  CONCLUSIONS
  Activation of cAMP signaling is a frequent event in canine cortisol-secreting ATs and may play a crucial role in both ACTH-independent cortisol production and tumor formation. To the best of our knowledge, this is the first report of potentially causative mutations in canine cortisol-secreting ATs.
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: M M J
authors.initials: MM
authors.lastname: Kool
authors.forename: S
authors.initials: S
authors.lastname: Galac
authors.forename: C G
authors.initials: CG
authors.lastname: Spandauw
authors.forename: H S
authors.initials: HS
authors.lastname: Kooistra
authors.forename: J A
authors.initials: JA
authors.lastname: Mol
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000662:veterinary*; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism / Q000662:veterinary*; D000818:Animals; D001483:Base Sequence; D003480:Cushing Syndrome / Q000235:genetics / Q000378:metabolism* / Q000662:veterinary*; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis / Q000662:veterinary; D004283:Dog Diseases / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D006651:Histocytochemistry / Q000662:veterinary; D006854:Hydrocortisone / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D012313:RNA / Q000737:chemistry / Q000235:genetics; D044101:Receptors, Melanocortin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary; D017422:Sequence Analysis, DNA
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D044385:GTP-Binding Protein alpha Subunits; D044101:Receptors, Melanocortin; D012313:RNA; D006854:Hydrocortisone
keywords: Adrenal; Cushing's syndrome; Dog; Gs alpha